PB1948: ACALABRUTINIB IN THE TREATMENT OF RICHTER SYNDROME
Authors: Tatyana Byalik, Gayane Tumyan, Natalia Natalia Kokosadze, Аkgul Odzharova, Evgeny Osmanov
Journal: HemaSphere (2023)

Topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical Background: Richter’s syndrome is an aggressive histologic transformation of chronic lymphocytic leukemia, most commonly to diffuse large B-cell lymphoma, occurring in about 2-15% of patients with CLL. Outcomes for patients with RS are generally poor with median overall survival of 5.9–11.4 months and ongoing unmet clinical need for effective therapies. B-cell receptor signaling through Bruton tyrosine kinase is one of the essential growth pathways for CLL. Acalabrutinib is a highly selective, potent BTK inhibitor has shown significant efficacy in relapsed/refractory and untreated CLL. Aims: improving the outcomes of patients with RS Methods: We reported 5 cases of Richter syndrome treated with acalabrutinib in combination with immunochemotherapy in the period from June 2020 to February 2023. Table 1 shows the characteristics of 5 CLL pts who developed biopsy-proven DLBCL. The median time to transformation from CLL was 33,8 months (range 4-66 months). Determination of clonal association with CLL by blot hybridization was not available, but in 4 pts the p53 expression was studied by immunohistochemical method to determine the pathogenetic pathway of RS development and the PD-1 expression confirm the clonal association with CLL Results: At the time of transformation, 2 pts were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with a suboptimal response, then acalabrutinib was added, 2 pts received 6 cycles of R-CHOP+ acalabrutinib and 1patient - 5 cycles R-CVP + acalabrutinib. The overall response was 80% (1 pts had a CR and 2 PR), stabilization of the tumor process was achieved in 1 patient. The 3 pts with CR and PR are currently receiving acalabrutinib, 1 prs had progression of DLBCL after 15 months of acalabrutinib therapy and 1 pts died from Сovid19- infection on the background of stabilization of the disease Acalabrutinib was well-tolerated; no patient required discontinuation as a result of adverse events. At the time of CLL diagnosis (table1) - Patient 1 2 3 4 5 Age, y 75 28 64 34 65 Sex M F M F M Rai stage II II II II II CLL therapy Rituximab monotherapyEfficacy - CR none FCG, 6 cycle Efficacy - CR FCR 6 cycles Efficacy - CRi none Time from last CLL therapy to RS diagnosis months 66 45 48 4 6 Localization of the tumor Peripheral, retroperitoneal LN, stomach Peripheral LN, nasal sinuses, upper palate Retroperitoneal LN, colon Tumor of the tongue root Oropharynx, right tonsil, peripheral and retroperitoneal LN Subtype GCB- type Non-GCB Non-GCB Non-GCB Non-GCB At the time of DLBCL diagnosis (table 1- continuation) - Patient 1 2 3 4 5 Age, y 82 32 69 35 66 WBC ×109/L 5,53 6,23 10,25 0,84 30,27 Hemoglobin, g/dL 12,4 11,6 10,7 6,6 14,0 Platelet ×109/L 178,0 294,0 120,0 41,0 331,0 Bone marrowlymphocytes, % 21 44 17.2 8.2 55 IGHV mutation status not possible to establish Unmutated Unmutated (CLL1 subgroup) not possible to establish Unmutated FISH Normal Normal Normal Normal Deletion of 17p13/TP53 Mutation TP53 No mutations No No No Mutation р.R248W in exon 7 Mutation NOTCH1 - Mutation c7544 No No Mutation c 7389 р53/PDL-1 expression + / + - +++/+++ ++/++ +++/+++ Related with CLL De novo unknown clonally related clonally related clonally related Duration of acalabrutinib therapy, months 27 20 15 9 10 Best response PR CR Clinical benefit Stable disease PR Status at most recent follow-up Аcalabrutinib therapy continues Аcalabrutinib therapy continues Death from the progression of DLBCL Death by COVID19 Аcalabrutinib therapy continues Summary/Conclusion: Our experience suggests that acalabrutinib in combination with immunochemotherapy has potential as a novel therapeutic approach for patients with Richter syndrome. Keywords: Chronic lymphocytic leukemia